Von Hippel-Lindau (VHL) disease is a neoplastic disorder with tumors of the central nervous system, kidneys, adrenals, pancreas, and retina. Clear cell renal carcinoma (RCC) is the most frequent cause of death. Interestingly, the VHL gene, recently cloned, plays a critical role in sporadic (i.e. non-VHL related) RCC, the most common cancer of the kidney, with defects in up to 70% of such tumors. Importantly, transfection of wild type VHL into renal cell lines lacking functional VHL abrogates their tumorigenicity. Some genes are known to be disregulated in renal cell cancer. In Preliminary Studies the PI has found that disregulation of one such gene, transforming growth factor alpha (TGF-alpha), is a consequence of VHL mutation. In other Preliminary Studies, the transcription factor Sp1 and the VHL protein itself have been identified as interacting partners for VHL. These observations will be extended as follows: Specific Aim 1: Dissection of the molecular pathway by which VHL represses TGF-alpha mRNA expression. Specific Aim 2: VHL-Sp interaction: structural definition, mechanistic studies and functional significance. Specific Aim 3: VHL-VHL interaction: structural definition and functional significance. These experiments will lead to a clearer understanding of VHL function at a molecular level and, in the long run, may lead to new therapies for RCC. Additionally, these studies on VHL tumor suppressor function will provide insights into tumor suppression action in general and a better understanding of mRNA half-life regulation, transcriptional control, and cellular protein localization, since VHL affects all of these processes.